Project Summary: Adoptive transfer of multiple stem cell types into failing human hearts has demonstrated safety however the beneficial effects in patients with cardiovascular disorders have been modest. Despite increasing use of stem cell based therapies, there is no consensus on the optimal stem cell type. Modest repair and improvement in patients with cardiac complications warrants identification of a novel stem cell population that possesses youthful phenotype and effectively repair the heart after myocardial environment. Recently we have shown in a mouse model that cortical bone derived stem cells (CBSCs) enhance cardiac function after myocardial infarction and these beneficial effects appear largely to be mediated by paracrine mechanisms. The fundamental basis of the project is to investigate whether observed cardioprotection is mediated by secretion of exosomes from CBSCs. Our preliminary data indicates that CBSCs derived exosomes recapitulate our earlier findings with CBSCs transplantation and demonstrate effective way for cardiac repair. The hypothesis of this research is to study the molecular contents (microRNA and paracrine factors) present in exosomes derived from cortical bone stem cells. Additionally, we will test various exosome delivery approaches together with the determination of optimal exosome dose in a large clinically relevant animal model. Our proposed study will provide information on CBSCs unique protective signature molecules carried by exosomes and swine animal model for heart repair that should provide basis for developing novel therapies for treating heart failure patients.